chemistry journal of moldova

N.Gorinchoy et al./Chem.J.Mold. 2008, 3 (1), 94-104This mechanism can be extended to the simultaneous action of two molecules. Indeed, if the first molecule S hasno pharmacophore, there will not be transformation to the product. Then the equilibrium (Boltzman distribution) allowsfor the second molecule to enter the intermediate complex:S + E SESE + S SSE P (8)If two molecules in a bimolecular docking to the receptor posses the pharmacophore, they may produce the necessaryaction that triggers the drug activity, albeit with lower probability than a single molecule with the pharmacophore. In theproblem of aquatic toxicity to fish under consideration, for instance, the molecule allyl chloride (II) with logLC 50= 1.20has no pharmacophore, while a 1,4-dichloro-2-butene (I) with logLC 50= -0.16 has the pharmacophore. The structure ofthese two molecules in Fig. 2 shows how two molecules of II produce the structure III which is similar to I and has thepharmacophore; hence the activity of II can be explained in this way.IClClIIClClIIIClFig. 2. Illustration of bimolecular activity: two active molecules of allyl chloride (II), which separately haveno pharmacophore, by stacking along the double bond produce a bimolecular structure (III) which is similar to1,4-dichloro-2-butene (I) and has the pharmacophore.Step 6. In accordance with the EC method techniques [8], the presence of toxicophore is only a necessarycondition of activity; the evaluation of activity quantitatively involves the regression analysis mentioned above. For the17 most active molecules the following relations for biological activity was employed [7, 8]:Ei Ereflog( LC50) log( LC50)ref 2.30259 Si[R] kT i (9)where (LC 50 ), and (LC 50 ) ref stand for numerical values of activity of the i-th compound and the reference compound,respectively, E iis the relative energy of the lowest energy conformer of the i-th compound that contains toxicophore,and S i[R] is a function of the electronic and geometric parameters of the substrate molecule.The parameters in the function S i[R] in Eq. (9) should be obtained from the condition of minimum differencebetween the calculated toxicity LC 50 ) i and the experimental values ( LC 50 ) i . The regression analysis was performedover the 17 toxicophore-containing molecules and the correlation coefficient as good as R 2 = 0.94 and R 2 = 0.92 in across-validated procedure was obtained with just three parameters of their electronic structure:i ref i ref i refSi[ R] k1(IImax IImax) k2(q q ) k3(C13 C13),(10)iwhere II max is the largest “interaction index” II in i-th molecule, q i is a Mulliken charge of the most electron-negativeatom near to the toxicophore atom T2 i i(within the radius of R < 2Å of the typical chemical bond length) and C 13 isthe matrix element of the ECSA corresponding to the distance (in Å) between the toxicophore atoms T1 i and T3 i ; T1,T2, T3, and T4 denote consecutively the four atoms in their ECSA (see eq. 3). The following values of the coefficientsminimize the expression (10):k 1 7.58; k 2 14.74;k 3 1.36 .(11)The theoretical values of toxicities calculated with this set of coefficients and those received in the leave-one-outcross-validation procedure are given in Table 3. The correlation between the experimental and calculated values of -log(LC 50) is presented graphically in Fig. 3.exp101